Although clinical cardiac transplantation is effective therapy for patients with end stage cardiac disease the current shortage of donor organs limits the efficacy of this treatment. One solution to the organ donor shortage is the use of animal organs for human transplantation (xenotransplantation). Presently the immunologic barrier to xenotransplantation preclude this as a viable alternative. In previous work in an animal model of allo-transplantation, immune tolerance has been produced by exposure of the recipient animal to allogeneic cells either at a time when the immune system is immature (fetal, neonatal) or by exposing a transiently immunosuppressed mature animal to antigen intrathymicaIly. This research plan seeks to extend these observations to a model of xenotransplantation using a rat donor and mouse recipient. This model is advantageous since the availability of molecular reagents allows study of the mouse immune system at the molecular level. The research plan mirrors previous work in the allotransplant model. The research will explore different methods of exposing the immature murine immune system to rat cells and the subsequent response to a vascularizedcardiac graft. In addition, pretreatment of adult murine recipients will be followed by exposure to donor cells and subsequent vascularized cardiac xenotransplantation.